Human pregnancy is a balance between supporting the conceptus and maintaining the health of the mother. Profound cardiovascular and immune system adaptations must occur throughout pregnancy for a successful outcome. The mechanisms and functions of many of these adaptations still allude our understanding; however, we do know that perturbations in both the cardiovascular and immune changes can have deleterious and sometimes devastating consequences to the pregnancy. This proposal will focus on the consequences to pregnancy of one external stress; cigarette smoking. Smoking during pregnancy has many negative outcomes, including an increased risk of early pregnancy loss, premature birth and intrauterine growth restriction. Infants born of mothers who smoked during pregnancy have an increased risk of developing Type 2 diabetes and obesity and suffer from an elevated frequency of chromosomal translocations. The cause and effect relationship between smoking and poor pregnancy outcome most likely occurs at multiple levels. We hypothesize that smoking enhances the inflammatory response that occurs naturally during pregnancy and pushes it out of balance, leading to vascular compromise and fetal and maternal morbidity. We will test our hypothesis by determining to what extent smoking influences the inflammatory response of both mother and fetus, investigate the influence of genetic background on smoking-related consequences and establish a mouse model to examine in utero effects of smoking. Despite concerted public health efforts to reduce cigarette smoking in this country, it remains a leading cause of morbidity and mortality. The prevalence of pregnant women who smoke ranges from 10 - 25%, with consequent long range health effects to both mother and infant. Successful completion of this proposal should significantly increase our understanding of smoking related morbidity and potentially guide public health professionals to segments of the population that would benefit from more aggressive public hearth intervention strategies.